Docosapentaenoic acid is one of rare unsaturated fatty acids of C22: 5n-3 contained in fish oil in trace amounts. Since a highly pure docosapentaenoic acid cannot be obtained in large quantities, physiological, medical, and nutritional studies thereof have lagged behind (Non Patent Literature 1).
The following facts have been reported with respect to this point (Non Patent Literature 2).
(1) Docosapentaenoic acid is inversely converted into icosapentaenoic acid in many tissues.
(2) Docosapentaenoic acid is effective in maintaining and promoting health.
(3) Docosapentaenoic acid is metabolized in platelets to provide hydroxydocosapentaenoic acid.
The above facts suggest the possibility of docosapentaenoic acid being converted in vivo into resolvin D4, which activates the immune system to exhibit anti-inflammatory action.
Non Patent Literature 3 reports the following.
(4) Rabbit platelet agglutination inhibiting action of docosapentaenoic acid is more potent than icosapentaenoic acid or docosahexaenoic acid, and therefore a clot formation suppressing effect can be expected.
(5) Docosapentaenoic acid has endothelial cell migration capability that is 10-times greater than icosapentaenoic acid. This is an important effect in wound healing.
Non Patent Literature 4 reports the following.
(6) Docosapentaenoic acid has a more potent action of reducing fatty acid synthase and malate synthase activity than icosapentaenoic acid.
(7) Docosapentaenoic acid possibly regulates a phenomenon of sustained improvement in signaling between two nerve cells by costimulation and age-related spatial learning.
Non Patent Literature 5 reports the following.
(8) Docosapentaenoic acid has angiogenesis suppressing action.
As discussed above, docosapentaenoic acid would play an important role in fields of alternative medicines and health food in the future and see increased demand therewith. Thus, development of a highly efficient production method including the present invention is an urgent problem to be solved toward the future. In recent years, biofunction of multivalent unsaturated fatty acids, especially icosapentaenoic acid and docosapentaenoic acid derived from fish oil, has drawn attention. The demand thereof is about to increase even more, including highly pure icosapentaenoic acid as a medicament. The demand for multivalent unsaturated fatty acids as supplements, mainly docosapentaenoic acid, is also about to expand. Meanwhile, resources for multivalent unsaturated fatty acids are in a declining trend in a global scale, such that search for a method of preservation thereof is an important problem to be solved. While most multivalent unsaturated fatty acids are currently dependent on fishery resources including fish, research related to a method of production with algae or plant matters is actively pursed. For instance, Monsanto has established a method of producing stearidonic acid, which is a precursor to icosapentaenoic acid, with genetically modified soybeans, and the method is already approved by the FDA. Methods of using a reaction to chemically extend multivalent unsaturated fatty acids or a microbe produced desaturase have also been reported. However, it is generally difficult to simultaneously conduct a carbon chain extending reaction and desaturation on a large amount of multivalent unsaturated fatty acids, which is not at an implementable stage at a practical production level beyond the laboratory level. A chemical synthesis method of multivalent unsaturated fatty acids by a carbon chain extending reaction has been reported. For example in Non Patent Literature 6, one methylene proton in a p-toluenesulfonylmethyl isocyanate molecule is pulled out with a base and the produced carbanion is reacted with saturated fatty acid methyl ester bromide to synthesize a new isocyanate having a carbon long chain, and a strong base such as sodium hydride is used to similarly replace the other proton of the methylene chain with an unsaturated chain. Lastly, lithium/ammonia/ethanol and methanol/hydrochloric acid are reacted to remove a toluene sulfonyl group and isonitrile group to synthesize a multivalent unsaturated fatty acid methyl ester. However, these methods are disadvantageous in that the total yield is low, and an expensive reagent or a reagent, which has a strong reactivity and is difficult to handle, must be used.
Meanwhile, Baba et al. have successfully synthesized tetracosahexaenoic acid with two more carbon atoms than docosahexaenoic acid ethyl ester through using docosahexaenoic acid ethyl ester as a starting material to produce alcohol by lithium aluminum hydride reduction and converting the alcohol to p-toluenesulfonic acid ester, and then converting the p-toluenesulfonic acid ester to iodide by a substitution reaction and, in the presence of a base, reacting diethylmalonate therewith to produce malonate ester, and subjecting the ester to alkaline hydrolysis, decarboxylation. (Non Patent Literature 7 and Non Patent Literature 8)
This reaction is also applied in a carbon chain extending reaction of linoleic acid or arachidonic acid. However, this method comprises many reaction steps and thus is not necessarily considered a practical method for large-scale production.
The method published by Ito et. al. in 2011 synthesizes tetracosahexaenoic acid with two more carbons in four steps from docosapentaenoic acid ethyl ester (Non Patent Literature 9). However, this method uses a reagent that is very unstable with respect to air called DIBAL-H and performs a reaction at a low temperature of −78° C. Thus, it is expected that scaling up the synthesis process would be difficult.